Scar formation during wound healing is a cosmetically undesired process, especially if the scars are formed on the face and other conspicuous or identity-determining parts of the body. Scar formation can also have health implications. As a prominent example, myocardial scar formation occurring after myocardial infarction impairs cardiac function by inducing cardiac remodeling, reducing cardiac compliance and compromising normal electrical conduction across the heart.
When we are injured, the body launches a complex rescue operation. Specialized cells called fibroblasts present just beneath the surface of the skin come into action, enter the provisional wound matrix (the clot) and start secreting collagen to close the wound as fast as possible. This matrix is initially soft and loaded with growth factors. The fibroblasts “crawl” around the matrix, pulling and reorganizing the fibers. The matrix grows stiffer, and at a certain point, the fibroblasts stop migrating and change into powerful contractile cells, anchoring themselves to the matrix and pulling the edges of the wound together.
Although this process will heal a wound quickly, it can also lead to a build-up of fibrous tissue. Following trauma to vital organs such as the heart, lung, liver and kidney, overzealous fibroblasts can continue to build fibrous strands, leading to scar tissue formation that can impair the organ's function. This condition, called “fibrosis”, can be fatal. Fibroblasts are also the culprits in problems caused by implants; if the implant is too smooth, it never becomes properly incorporated into the connective tissue. However, if it is too rough, scar tissue develops around it and the tissue will not function properly. Occasionally, following plastic surgery, unsightly excessive scar tissue can develop in the skin as well. The process can also cause problems in mesenchymal stem cell cultures; if the culture's substrate is stiff, considerable efforts have to be made to prevent the stem cells from turning prematurely into fibroblasts instead of the desired cell type. Controlling the rigidity of the cell culture is therefore critical.
A fibroblast is a type of cell that synthesizes and maintains the extracellular matrix of many animal tissues. Fibroblasts provide a structural framework (stroma) for many tissues, and play a critical role in wound healing. They are the most common cells of connective tissue in animals.
The main function of fibroblasts is to maintain the structural integrity of connective tissues by continuously secreting precursors of the extracellular matrix. Fibroblasts secrete the precursors of all the components of the extracellular matrix, primarily the ground substance and a variety of fibers. The composition of the extracellular matrix determines the physical properties of connective tissues.
Fibroblasts are morphologically heterogeneous with diverse appearances depending on their location and activity. Though morphologically inconspicuous, ectopically transplanted fibroblasts can often retain positional memory of the location and tissue context where they had previously resided, at least over a few generations.
Unlike the epithelial cells lining the body structures, fibroblasts do not form flat monolayers and are not restricted by a polarizing attachment to a basal lamina on one side, although they may contribute to basal lamina components in some situations (e.g. subepithelial myofibroblasts in intestine may secrete the α-2 chain carrying component of the laminin, which is absent only in regions of follicle associated epithelia which lack the myofibroblast lining). Fibroblasts can also migrate slowly over substratum as individual cells, again in contrast to epithelial cells. While epithelial cells form the lining of body structures, it is fibroblasts and related connective tissues which sculpt the “bulk” of an organism.
Nakao and colleagues studied the effects of annexin A5 on normal human keratinocytes (NHK) in vitro and in a surgical wound assays for reepithelialization (Nakao et al.: A new function of calphobindin I (annexin A5): Promotion of both migration and urokinase-type plasminogen activator activity of normal human keratinocytes; Eur. J. Biochem. (1994) 223: 901-908). These in vitro studies showed promotion by Calphobindin of both uPA synthesis of epithelial keratinocytes and their migration (but not proliferation). Topical application of Calphobindin to cutaneous wounds in rat skin appeared to promote reepithelialization in these experiments.
Watanabe and colleagues have reported that Annexin A5 promotes corneal epithelial wound healing both in vitro and in vivo and that upregulation of uPA release from corneal epithelial cells may contribute to this effect of annexin A5 (Watanabe et al.; Promotion of Corneal Epithelial Wound Healing In Vitro and In Vivo by Annexin A5; Invest. Ophthalmol. Ms. Sci. 2006 47: 1862-1868).
However, these authors do not suggest to use annexins pharmaceutically in the context of scar formation.